Upcoming Events

Archives

Vacancies

BackgroundMetabolic diseases are a burden on the European population and health care system. It is increasingly recognised that individual differences with respect to history, lifestyle, and genetic make-up affect disease progression and treatment response. A Systems Medicine approach, based on computational models fed with individual patient data, has the potential to provide the basis for a personalised diagnosis and treatment strategy. The PoLiMeR consortium (Polymers in the Liver: Metabolism and Regulation) has identified the inherited, liver-related diseases of glycogen and lipid metabolism as the ideal starting point for innovative research training in personalised ‘Systems Medicine’. These diseases are life-threatening for children. Since each specific disease is rare, research efforts are diluted. Our system-based perspective opens possibilities for the application of novel drugs and diagnostic tools to a range of different diseases.

To advance diagnostics and treatment of metabolic diseases beyond the state-of-the-art, a new generation of scientists is needed. The complexity of the metabolic network and its aberrant behaviour in disease require truly interdisciplinary researchers, trained in the three ‘pillars of Systems Medicine’: experimental, computational and clinical research. PoLiMeR aims to train you as a talented PhD student in this field. We bring together clinical, academic, and industrial experts on inherited metabolic diseases, computational modelling of the entire human metabolism, organ-on-chip technology, and detailed metabolic profiling, located in Germany, Luxembourg, Sweden, Norway, and the United Kingdom.

As a PhD student in this project you will be part of a highly international team of young researchers. You will have your individual research project at your host organisation, focusing on your discipline of interest. To complement your specialized training, you will do internships at a complementary PoLiMeR partner organization. In addition, you will follow advanced interdisciplinary courses by leaders in the field of Systems Medicine. Thus, you will be trained to become a Systems-Medicine expert, with expertise in computational and wet-lab techniques, who can collaborate between clinical, academic, and industrial environments.

Are you interested? Please, check the 5 PhD positions that are still open in the PoLiMeR project!

PhD positions

Enzyme catalysis at the polymer surfaceGlycogen is a glucose-based polymer, comprising linear and branched components in a tree-like arrangement. Hence, an enzyme acting upon glycogen can cleave or rearrange the polymer backbone at multiple sites. The challenge will be to develop novel experimental and computational tools that can resolve spatiotemporal aspects of enzyme catalysis at the complex polymer surface, and apply these to clinical samples and data to identify bottlenecks and therapeutic targets.

The PhD student will develop a computational model to study overall dynamics of glycogen formation and analyse which parameters determine the structural properties of glycogen, such as branching pattern and size. The PhD student will reproduce metabolic disorders related to glycogen metabolism and develop intervention strategies how to counteract glycogen-related metabolic disorders by drug applications.

Combinatorial explosion of molecular speciesClassically, enzymes are thought to have a specific affinity for one well-defined substrate. In contrast, enzymes acting on larger molecules catalyse the conversion of a functional group in the substrate with a lesser specificity for the remaining part of the molecule. This promiscuity results in a combinatorial explosion of different molecular species, particularly in lipid metabolism. The challenge is to develop innovative analytical methods and genome-scale modelling approaches to analyse and interpret complex lipid profiles in a meaningful way, and apply these to clinical samples and data to identify novel causes of patient-to-patient variability.

The PhD student will develop novel analytical methods for lipid profiling, and thereby will focus on detailed analysis of modified lipidsand to identify structural isomers.This will be achieved using hydrophilic interaction chromatography (HILIC) or normal phase liquid chromatography (NPLC)-based separation coupled to a reversed-phase liquid chromatography (RPLC)-mass spectrometry analysis. The methods developed will be miniaturised to allow the analysis of biomass-limited samples, such as patient-derived iPS hepatocytes or organ-on-a-chip samples.

The PhD student will develop a novel approach to represent promiscuous enzymes (enzymes acting on lipid classes rather than on single lipid species) more efficiently in a genome-scale model (GEM). This innovation will be implemented in a comprehensive genome-scale model of human metabolism. The problem of combinatorial explosion of possible lipid molecular species in current computational models will be addressed by dividing the existing reactions for synthesis of complex lipids into a set of modular synthesis and degradation reactions, based on the concept of conserved moieties, resulting in a stoichiometric matrix that admits integral flows (integer reaction rates). Each integral flow shall represent the synthesis and degradation of a different combination of lipid molecular species. The PhD student will map lipidomics data in the metabolic network analyse computationally different disease specific scenarios.

Pathway dynamicsIf enzymes catalyse multiple reactions, alternative substrates compete with each other for binding to the enzyme, thereby inhibiting each other’s conversion. This implies that only a fraction of the total enzyme capacity is used for a specific reaction. At the level of metabolic pathways and networks this causes feedback and feedforward inhibition and may lead to complex dynamics, which has hitherto hardly been explored. The challenge will be to develop novel experimental tools and computational models to analyse the impact of substrate competition on pathway dynamics, and apply these to patient samples and data to identify putative therapeutic targets

PhD student 4: Interplay between coenzyme and energy metabolism in fatty-acid oxidation defectsHost organisation: University of Bergen, NO
contact: Mathias.Ziegler[at]uib.no

The PhD student will identify alterations of NAD and CoA coenzyme metabolism in mitochondrial fatty-acid oxidation (mFAO) deficient liver cells. Furthermore, the PhD student will modulate the availability of these coenzymes by pharmacological and genetic interventions and analyse the impact on energy metabolism, using metabolomics and 13C-fluxomics. The interventions will be done in cell cultures of mFAO-deficient hepatocytes or patient-derived fibroblasts.

The PhD student will focus on construction and validation of a dynamic model of lipid synthesis based on ordinary differential equations and detailed kinetic data. Patients with defects in the mitochondrial fatty-acid oxidation (mFAO) accumulate acyl-CoA esters which are substrates for chain elongation into longer lipids. The PhD student will connect the lipid synthesis model to an existing and experimentally validated mFAO model and explore pathway stability and lipid profiles in various mFAO disorders and at different diets.

Data and model managementA key challenge in Systems Medicine research is making the extremely diverse data FAIR. FAIR means Findability, Accessibility, Interoperability and Reusability of data. Within this project we base ourselves on the FAIRDOMHub, a platform for FAIR data, and explore improving the Findability of data using information retrieval methods. How can we enable users to store their results in a way that the results are most easily found, even if the query is imprecise?

PhD student 6: Data and model management and information retrievalHost organisation: HITS gGmbH, Heidelberg DE
contact: wolfgang.mueller[at]h-its.orgYou will be employed and do the research at HITS. In addition you will be registered at the University Medical Center Groningen (NL) to obtain the PhD degree.

The PhD student will provide FAIR data management services to the PoLiMeR consortium based on the FAIRDOM Hub (the data sharing site hosted at HITS) and on GitLab. The PhD student will use the database generated in the PoLiMeR project together with pre-existing and public data in the to determine how changes in data collection, metadata quality and data feature extraction affect the information that can be found. The PhD student will seek to improve existing tools for data collection as well as querying at critical points.

We are looking for graduates in computer science who are aiming for a Doctorate. This topic is particularly interesting in that it provides quite general challenges (How to I tailor information retrieval and information storage algorithms such that they work best in combination?); at the same time, there are *real* users to cater to. These users can help in finding out the best combination of data enrichment/search algorithm in real life, in an exciting application area: The life sciences.

Eligible candidates for a PhD position in the PoLiMeR training network should have the following qualifications:

A(n) (almost) completed master degree in a discipline relevant to the PhD position(s) for which you apply.

Strong motivation for scientific research in an interdisciplinary and international environment

Excellent English presentation and writing skills

Good organisational and communication skills, being a team-player

Successful candidates must fulfil the criteria defined by the European Commission:

As an Early Stage Researcher, you have to be in the first four years of your research career and have not been awarded a doctoral degree at the time of recruitment.

At the time of recruitment by the host organisation, researchers must not have resided or carried out their main activity (work, studies, etc.) in the country of their host organisation for more than 12 months in the 3 years immediately prior to the reference date.

The start of the PhD projects is envisaged between April 2019 and September 2019.

Application and contact

You are invited to apply if you are interested in one or more of the PhD positions. Please submit your CV and motivation letter via the application form. Please indicate in your motivation for which PhD position(s) you are applying. You can apply until 18 February 2019.

For more information about a specific position please contact the person indicated for that position.